Methods of protection from toxicity of alpha emitting elements during radioimmunotherapy

Abstract

Provided herein are methods of reducing nephrotoxicityfrom at least one alpha particle-emitting daughter of actinium-225 during radioimmunotherapeutic treatment for a pathophysiological condition, methods of improving radioimmunotherapeutic treatment of cancer and methods of increasing the therapeuticindex of an actinium-225 radioimmunoconjugate during treatment of a pathophysiological condition. Adjuvants effective for preventing accumulation of 225 Ac daughters within the kidneys are administered during treatment with an actinium-225 radioimmunoconjugate to reduce nephrotoxicity. Examples of adjuvants are chelators, diuretics and/or competitive metal blockers.

What is claimed is:  
     
         1 . A method of reducing nephrotoxicity in an individual during radioimmunotherapeutic treatment of a pathophysiological condition, comprising: 
 administering a pharmacologically effective dose of at least one adjuvant effective for preventing accumulation of a metal in kidneys;    administering an actinium-225 radioimmunoconjugate to treat the pathophysiological condition; and    preventing accumulation of alpha particle-emitting daughters of said actinium-225 within the kidneys of the individual via interaction between said adjuvant and said  225 Ac daughters or the kidney tissue or a combination thereof thereby reducing nephrotoxicity during the radioimmunotherapeutic treatment.    
     
     
         2 . The method of  claim 1 , wherein said adjuvant(s) is administered prior to administering said actinium-225 radioimmunoconjugate, said adjuvant(s) continuing to be administered after said actinium-225 radioimmunoconjugate.  
     
     
         3 . The method of  claim 1 , wherein said adjuvant is a chelator, a diuretic, a competitive metal blocker, or a combination thereof.  
     
     
         4 . The method of  claim 3 , wherein said chelator is 2,3 dimercapto-1-propane sulfonic acid, meso 2,3-dimercapto succinic acid, diethylenetriamine pentaacetic acid, calcium diethylenetriamine pentaacetic acid, or zinc diethylenetriamine pentaacetic acid.  
     
     
         5 . The method of  claim 3 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex or other loop diuretic.  
     
     
         6 . The method of  claim 3 , wherein said competitive metal blocker is bismuth subnitrate or bismuth subcitrate.  
     
     
         7 . The method of  claim 1 , wherein said  225 Ac daughter is bismuth-213, francium-221 or a combination thereof.  
     
     
         8 . The method of  claim 1 , wherein said actinium-225 radioimmunoconjugate comprises an actinium-225 bifunctional chelant and a monoclonal antibody.  
     
     
         9 . The method of  claim 8 , wherein said actinium-225 radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         10 . The method of  claim 1 , wherein said pathophysiological condition is a cancer or an autoimmune disorder.  
     
     
         11 . The method of  claim 1 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         12 . The method of  claim 11 , wherein said cancer is myeloid leukemia.  
     
     
         13 . A method of reducing nephrotoxicity in an individual during radioimmunotherapeutic treatment a pathophysiological condition, comprising: 
 administering a pharmacologically effective dose of a chelator;    administering an actinium-225 radioimmunoconjugate to treat the cancer; and    preventing accumulation of bismuth-213 daughters of said actinium-225 within the kidneys of the individual by scavenging thereof with said chelator thereby reducing nephrotoxicity during the radioimmunotherapeutic treatment.    
     
     
         14 . The method of  claim 13 , wherein said chelator is administered prior to administering said  225 Ac radioimmunoconjugate, said chelator continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         15 . The method of  claim 13 , wherein said chelator is 2,3 dimercapto-1-propane sulfonic acid, meso 2,3-dimercapto succinic acid, diethylenetriamine pentaacetic acid, calcium diethylenetriamine pentaacetic acid, or zinc diethylenetriamine pentaacetic acid.  
     
     
         16 . The method of  claim 13 , further comprising: 
 administering a pharmacologically effective dose of a diuretic; and    preventing accumulation of francium-211 daughters of said actinium-225 within the kidneys of the individual by inhibiting reabsorption of francium-211 therein with said diuretic thereby reducing nephrotoxicity during the radioimmunotherapeutic treatment.    
     
     
         17 . The method of  claim 16 , wherein said diuretic is administered prior to administering said  225 Ac radioimmunoconjugate, said diuretic continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         18 . The method of  claim 16 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex, or other loop diuretic.  
     
     
         19 . The method of  claim 13 , wherein said  225 Ac radioimmunoconjugate comprises an actinium-225 bifunctional chelant and a monoclonal antibody.  
     
     
         20 . The method of  claim 19 , wherein said  225 Ac radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         21 . The method of  claim 13 , wherein said pathophysiological condition is a cancer or an autoimmune disorder.  
     
     
         22 . The method of  claim 21 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         23 . The method of  claim 22 , wherein said cancer is myeloid leukemia.  
     
     
         24 . A method of reducing nephrotoxicity in an individual during radioimmunotherapeutic treatment of a pathophysiological condition, comprising: 
 administering a pharmacologically effective dose of a diuretic;    administering an actinium-225 radioimmunoconjugate to treat the cancer; and    preventing accumulation of francium-211 daughters of said actinium-225 within the kidneys of the individual by inhibiting reabsorption of francium-211 therein with said diuretic thereby reducing nephrotoxicity during the radioimmunotherapeutic treatment.    
     
     
         25 . The method of  claim 24 , wherein said diuretic is administered prior to administering said  225 Ac radioimmunoconjugate, said diuretic continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         26 . The method of  claim 24 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex, or other loop diuretic.  
     
     
         27 . The method of  claim 24 , wherein said  225 Ac radioimmunoconjugate comprises an actinium-225 bifunctional chelant and a monoclonal antibody.  
     
     
         28 . The method of  claim 27 , wherein said  225 Ac radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         29 . The method of  claim 24 , wherein said pathophysiological condition is a cancer or an autoimmune disorder.  
     
     
         30 . The method of  claim 29 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         31 . The method of  claim 30 , wherein said cancer is myeloid leukemia.  
     
     
         32 . A method of improving radioimmunotherapeutic treatment of cancer in an individual, comprising: 
 administering a pharmacologically effective dose of a chelator;    administering an actinium-225 radioimmunoconjugate; and    scavenging bismuth-213 daughters of the actinium-225 with said chelator to reduce nephrotoxicity in the individual during the treatment thereby increasing the therapeutic index of the actinium-225 to improve the treatment for said cancer.    
     
     
         33 . The method of  claim 32 , wherein said chelator is administered prior to administering said  225 Ac radioimmunoconjugate, said chelator continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         34 . The method of  claim 32 , wherein said chelator is 2,3 dimercapto-1-propane sulfonic acid, meso 2,3-dimercapto succinic acid, diethylenetriamine pentaacetic acid, calcium diethylenetriamine pentaacetic acid, or zinc diethylenetriamine pentaacetic acid.  
     
     
         35 . The method of  claim 32 , further comprising: 
 administering a pharmacologically effective dose of a diuretic; and    inhibiting renal uptake of francium-211 daughters of the actinium-225 with said diuretic to reduce nephrotoxicity in the individual during the treatment thereby increasing the therapeutic index of the actinium-225 to improve the treatment for-said cancer.    
     
     
         36 . The method of  claim 35 , wherein said diuretic is administered prior to administering said  225 Ac radioimmunoconjugate, said diuretic continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         37 . The method of  claim 35 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex, or other loop diuretic.  
     
     
         38 . The method of  claim 35 , wherein said  225 Ac radioimmunoconjugate comprises an actinium-225 bifunctional chelant and a monoclonal antibody.  
     
     
         39 . The method of  claim 38 , wherein said  225 Ac radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         40 . The method of  claim 35 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         41 . The method of  claim 40 , wherein said cancer is myeloid leukemia.  
     
     
         42 . A method of improving radioimmunotherapeutic treatment of cancer in an individual, comprising: 
 administering a pharmacologically effective dose of a diuretic;    administering an actinium-225 radioimmunoconjugate; and    inhibiting renal uptake of francium-211 daughters of the actinium-225 with said diuretic to reduce nephrotoxicity in the individual during the treatment thereby increasing the therapeutic index of the actinium-225 to improve the treatment for said cancer.    
     
     
         43 . The method of  claim 42 , wherein said diuretic is administered prior to administering said  225 Ac radioimmunoconjugate, said diuretic continuing to be administered after said  225 Ac radioimmunoconjugate.  
     
     
         44 . The method of  claim 42 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex, or other loop diuretic.  
     
     
         45 . The method of  claim 42 , wherein said  225 Ac radioimmunoconjugate comprises an actinium-225 bifunctional chelant and a monoclonal antibody.  
     
     
         46 . The method of  claim 45 , wherein said  225 Ac radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         47 . The method of  claim 42 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         48 . The method of  claim 47 , wherein said cancer is myeloid leukemia.  
     
     
         49 . A method of increasing the therapeutic index of an actinium-225 radioimmunoconjugate during treatment of a pathophysiological condition in an individual comprising: 
 inhibiting renal uptake of at least one alpha particle-emitting daughter of actinium-225 whereby nephrotoxicity is reduced during the treatment thereby increasing the therapeutic index of said actinium-225 radioimmunoconjugate.    
     
     
         50 . The method of  claim 49 , wherein inhibiting renal uptake of said  225 Ac daughter(s) comprises: 
 administering a pharmacologically effective amount of an adjuvant comprising: 
 a chelator to scavenge said  225 Ac daughters therewith; or  
 a diuretic to inhibit reabsorption of said  225 Ac daughters within a kidney; or  
 a competitive metal blocker to prevent binding of said  225 Ac daughters within a kidney; or  
 a combination thereof.  
   
     
     
         51 . The method of  claim 50 , wherein said chelator and/or said diuretic and/or said competitive metal blocker are administered prior to treatment with said actinium-225 radioimmunoconjugate, said chelator and/or said diuretic continuing to be administered after said actinium-225 radioimmunoconjugate is administered to the individual.  
     
     
         52 . The method of  claim 50 , wherein said chelator is 2,3 dimercapto-1-propane sulfonic acid, meso 2,3-dimercapto succinic acid, diethylenetriamine pentaacetic acid, calcium diethylenetriamine pentaacetic acid, or zinc diethylenetriamine pentaacetic acid.  
     
     
         53 . The method of  claim 50 , wherein said diuretic is furosemide, chlorthiazide, hydrochlorothiazide, bumex, or other loop diuretic.  
     
     
         54 . The method of  claim 50 , wherein said competitive metal blocker is bismuth subnitrate or bismuth subcitrate.  
     
     
         55 . The method of  claim 50 , wherein said chelator scavenges the  225 Ac daughter bismuth-213.  
     
     
         56 . The method of  claim 50 , wherein said diuretic inhibits reabsorption of the  225 Ac daughter francium-211.  
     
     
         57 . The method of  claim 50 , wherein said competitive metal binder prevents binding of the  225 Ac daughter bismuth-213.  
     
     
         58 . The method of  claim 49 , wherein said actinium-225 radioimmunoconjugate is [ 225 Ac] DOTA-HuM195.  
     
     
         59 . The method of  claim 49 , wherein said pathophysiological condition is a cancer or an autoimmune disorder.  
     
     
         60 . The method of  claim 59 , wherein said cancer is a solid cancer, a disseminated cancer or a micrometastatic cancer.  
     
     
         61 . The method of  claim 60 , wherein said cancer is myeloid leukemia.